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Biomedical subjects

M Talpaz

Publications and source records attributed to M Talpaz.

At least 127 records · Page 7Linked to original sources
PubMed1996

Phase II trial of recombinant human interleukin-2 and interferon-alpha-2a: implications for the treatment of patients with metastatic melanoma.

BACKGROUND: An intensive in-patient Phase II study of continuous infusion recombinant human interleukin-2 (rhIL-2) 3 X 10(6) Roche units (9 MIU/m2)/day plus intramuscular injection of interferon-alpha-2a (rIFN-alpha-2a) 5 x 10(6) U/m2/day, four consecutive days per week, was performed to determine whether four consecutive weeks of treatment every 6 to 8 weeks might yield a response rate of 30 to 40%, supporting an additive or synergistic effect of these agents in patients with metastatic melanoma. METHODS: Eligibility was limited to otherwise healthy metastatic melanoma patients with no brain metastases. Tumor sites were measured at six-week intervals. Toxicity was recorded using the National Cancer Institute's common toxicity criteria. RESULTS: From 1988 through 1989, 23 patients received 47 courses of rhIL-2 plus rIFN-alpha-2a. Fifteen patients (65%) had visceral metastases. Eight patients (35%) had prior systemic chemotherapy. There were two partial responses, both after one course, for a response rate of 8% (95% confidence interval: 1% to 28%). A previously untreated patient had more than 90% diminution in extensive liver, adrenal, duodenal, and soft tissue metastases lasting 9 months. A second patient, who had failed prior chemotherapy, had a 50% reduction in lymph node metastases lasting 8 months. Median overall survival was 10.4 months (21 and 70+ months for the two responders). Cumulative reversible toxicities of debilitating fatigue, malaise, depression, poor appetite, and acute toxicities of hypotension, oliguria, infection, and cortical dysfunction were responsible for dose modifications in 16% of 188 anticipated weeks of treatment, usually near the end of the second or subsequent treatment courses. CONCLUSIONS: This study demonstrates a low response rate and lack of additive benefit for rhIL-2 and rIFN-alpha-2a administered intensively in metastatic melanoma patients. Since this biotherapy regimen, in the same dose and weekly schedule, has yielded substantial clinical activity with chemotherapeutic agents, this activity cannot be significantly attributed to the independent activity of rhIL-2 plus rIFN-alpha-alone.

Adult↗
PubMed1996

Role of granulocyte-macrophage colony-stimulating factor in Philadelphia (Ph1)-positive acute lymphoblastic leukemia: studies on two newly established Ph1-positive acute lymphoblastic leukemia cell lines (Z-119 and Z-181).

Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) is a malignant disorder characterized by a poor prognosis. In recent years hematopoietic growth factors have been used to recruit myeloid leukemia blasts into the proliferative phase of the cell cycle and as supportive agents, both with cytotoxic regimens and in the setting of bone marrow transplantation. This approach prompted us to investigate whether myeloid growth factors have a role in Ph1 positive ALL. To do this, we utilized two newly established Ph1-positive cell lines, Z-119 and Z-181. Both lines have L2 morphology, ultrastructural characteristics of lymphoblasts and typical B-lineage surface markers identical to those observed in the two Ph1-positive ALL patients from whom they were derived. In addition, a single rearranged immunoglobulin heavy-chain gene (JH) band was found in both cell lines by Southern blot analysis, confirming B-cell clonality. Cytogenetic analysis of the two lines revealed t(9;22). Polymerase chain reaction (PCR) amplified cDNA from both Z-119 and Z-181 cells revealed an e1--a2 BCR-ABL junction, and p190BCR-ABL protein was detected in them by the immune complex kinase assay. Both cell lines produce interleukin (IL)-1 beta, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF), but neither IL-1 beta, G-CSF, their corresponding antibodies and inhibitory molecules, nor GM-CSF, affected the cell lines' growth. However, GM-CSF neutralizing antibodies inhibited Z-181 but not Z-119 colony formation in a dose-dependent fashion by up to 77% and addition of GM-SCF reversed this inhibitory effect. Receptor studies with radiolabeled GM-CSF demonstrated specific binding to Z-181 but not to Z-119 cells, and Scatchard analysis revealed that Z-181 cells express high-affinity GM-CSF receptors. Furthermore, PCR analysis showed that Z-181 but not Z-119 bears the transcript for the GM-CSF receptor. Finally, studies using PH1-positive ALL patients' marrow cells revealed similar data. In 3 of 8 samples we detected significant concentrations of GM-CSF (7.5-13 pg/2 x 10(7) cells) and in 2 of 3 cases GM-CSF significantly stimulated Ph1-positive ALL colony proliferation. These data suggest that Ph1-positive ALL cells may produce GM-CSF, express GM-CSF receptors and thus show a proliferative response to this cytokine.

Adult↗
PubMed1996

Chronic myelogenous leukemia: a review.

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder with an initially chronic course lasting for 3-5 years. It eventually transforms into accelerated and blastic phases, which are generally fatal. CML was one of the first diseases in which a specific chromosomal abnormality was identified, a t(9;22)(q34;q11) or Philadelphia chromosome. CML had been traditionally treated with conventional chemotherapy with hydroxyurea or busulfan. Although these agents can achieve hematologic remissions in most patients, no evidence of sustained disappearance of the chromosomal abnormality was evident. Interferon alpha (IFN-alpha) has been able to achieve hematologic and cytogenic remissions in a significant number of patients, and recent studies show a survival advantage for patients treated with IFN-alpha compared with those treated with conventional chemotherapy. The results of these studies are discussed, and the reasons for discordance among different investigators analyzed in this review. Allogeneic bone marrow transplantation (BMT) may be curative in some patients with CML. The benefits and limitations of this approach in the treatment of CML are also discussed and the results of different alternatives compared. Other alternatives of therapy, including newer chemotherapeutic agents, combinations of IFN-alpha with other agents, and autologous BMT, are presented. The availability of very sensitive techniques for detection of the Philadelphia chromosome at the molecular level has allowed the detection of minimal residual disease. The information available on these measurements is also analyzed. Finally, we discuss the alternatives for patients with accelerated and blastic phase CML, as well as the clinical characteristics and prognosis for patients with Philadelphia-chromosome-negative CML.

Adult↗
PubMed1996

Result of interferon-alpha therapy in patients with chronic myelogenous leukemia 60 years of age and older.

PURPOSE: To determine the response rate to interferon-alpha (IFN-alpha) in patients with chronic myelogenous leukemia (CML) aged 60 years and older. PATIENTS AND METHODS: Patients with CML aged 60 years and older included in all protocols with INF-alpha therapy for chronic phase CML at the M.D. Anderson Cancer Center were analyzed. They were treated with human leukocyte or recombinant human IFN-alpha 5x10(6) U/m2 daily alone or in combination with hydroxyurea or IFN gamma. The clinical characteristics of the patients were analyzed and their hematologic and cytogenetic responses to IFN-alpha and survival from the initiation of therapy were determined. Results were compared with those of younger patients treated in the same protocols. Treatment-related toxicity was also analyzed. RESULTS: Thirty-five of 274 (13%) patients included in trials of IFN-alpha-based regimens for CML were 60 years and older. Older patients had a higher percentage of bone marrow blasts (P = 0.04) and basophils (P = 0.09) than younger patients. Sixty-nine percent achieved a complete hematologic remission with IFN-alpha therapy, and 51% had a cytogenetic response, which was major in 26% and complete (Philadelphia chromosome-positive cells = 0%) in 20%, Their median survival was 64 months, and the estimated 5-year survival rate was 62%. These results were not different from those in younger patients. Twenty-two patients (63%) had at least grade 2 toxicity requiring dose adjustment. The most frequent side effects were neurotoxicity in 31% and chronic fatigue in 29%. CONCLUSIONS: Patients with CML 60 years of age and older respond well to IFN-alpha therapy, but experience more toxicity. This therapy should be considered for these patients if they are otherwise in good condition, with careful attention to IFN-alpha toxicity and its management.

Age Factors↗
PubMed1996

Comparison of bcr-abl protein expression and Philadelphia chromosome analyses in chronic myelogenous leukemia patients.

The Philadelphia chromosome (Ph) is found in most chronic myelogenous leukemia (CML) patients. The bcr-abl oncoprotein (P210 or P185), the product of the fused bcr-abl gene produced by the Ph, is known to be the major factor in initiation and maintenance of the leukemic state in these types of leukemias. The authors have devised a Western blot test to detect and quantitate the bcr-abl oncoprotein in blood and bone marrow cells. The authors analyzed 1,155 peripheral blood samples from CML patients, for which there were same day Ph data, to determine if there was a correlation between bcr-abl protein levels and the percentage of Ph. A ratio of bcr-abl protein (P210 or P185) to normal abl protein (P145), the latter is ubiquitously expressed in all blood cells, has been established as a criterion for quantitating bcr-abl levels. The bcr-abl/abl protein ratio from 399 patient who were 100% Ph-positive had a mean of 2.47 (standard error [SE] of +/- 0.05); no false negatives were detected. A decreasing ratio was found in patients with decreasing percentages of Ph. The relationship between the ratio of bcr-abl/abl proteins to the percentage of Ph-positive cells was nearly linear in 392 patients with Ph percentages between 5% to 95% (r = 0.97, P < .001). For patients in remission with no detectable Ph, the bcr-abl/abl ratio had a mean of 0.01 (SE = 0 +/- 0.00). The level of bcr-abl expression in samples from peripheral blood and bone marrow also were compared. The results indicated that the amount of bcr-abl protein within peripheral blood is usually similar to that in marrow. In conclusion, quantitation of the bcr-abl oncoprotein in peripheral blood cells or marrow cells as measured by a Western blot assay provides reliable data for both diagnosis and monitoring patients with pH-chromosome positive leukemia.

Blotting, Western↗
PubMed1996

Significance of cytogenetic clonal evolution in chronic myelogenous leukemia.

PURPOSE: To describe the incidence and significance of clonal evolution patterns. PATIENTS AND METHODS: We analyzed 264 patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who developed clonal evolution between 1967 and 1993. RESULTS: The median survival time following clonal evolution was 19 months. Factors associated with worse survival (P < .01) were as follows: chromosome 17 abnormality or chromosomal translocations other than Ph, high percentage of abnormal metaphases, longer time to clonal evolution, and presence of other accelerated-phase features. A recursive partitioning technique (CART) identified different risk groups. The best group (37 patients; no chromosome 17 abnormality, abnormal metaphases < 16%, and interval to clonal evolution < or = 24 months) had an estimated median survival time of 54 months. The worst two groups included 27 patients with chromosome 17 abnormalities and > or = 36% abnormal metaphases (estimated median survival time, 6 months), and 22 patients with other accelerated features and > or = 16% abnormal metaphases (estimated median survival time, 7 months). The intermediate group had an estimated median survival time that ranged from 13 to 24 months. Prior interferon therapy evaluated within risk groups showed a significant survival advantage only in the intermediate-risk group. A multivariate analysis showed similar results, and identified the following independent poor prognostic variables: chromosome 17 abnormality, percentage of abnormal metaphases (cutoff, 24%), longer time to clonal evolution (cutoff, 24 months), other accelerated-phase features, and no prior interferon therapy. Patients with none, one, two, three, or more of the first four features had median survivals times of 51, 24, 14, and 7 months, respectively. CONCLUSION: The prognostic significance of clonal evolution in CML is not uniform and is related to the specific abnormality, time to its development, its predominance in metaphases, and the presence of other accelerated features, and it may be modified by specific therapies.

Bone Marrow Transplantation↗
PubMed1996

Practical guidelines for the management of chronic myelogenous leukemia with interferon alpha.

Interferon-A (IFN-A) is an effective agent in the treatment of chronic myelogenous leukemia (CML). Hematologic remissions occur in the majority of patients with newly diagnosed disease, and cytogenetic remissions may occur in up to 50% of patients. Several studies have shown a correlation between the dose of IFN-A and achievement of a major cytogenetic response; this response has also been correlated with prolonged survival. However, IFN-A may be associated with significant side effects that reduce enthusiasm for the use of this drug, produce difficulties in patient compliance, and limit the dose delivered to the patient, thus resulting in ineffective use of IFN-A. Experience with this drug has led to a refinement in techniques for initiation of therapy as well as interventions to deal with side effects. These strategies are often not discussed in publications dealing with response rates and survival. In this review we discuss strategies to minimize toxicity and improve the effectiveness of IFN-A in the treatment of CML.

Antineoplastic Agents↗
PubMed1996

Human recombinant interferon-inducible protein-10 inhibits the proliferation of normal and acute myelogenous leukemia progenitors.

Recombinant human interferon-inducible protein-10 (rIP-10) has been recently identified, purified and shown to suppress the multiplication of normal marrow early hemopoietic progenitors. In the present study we investigated the effect of rIP-10 on different normal and acute myelogenous leukemia (AML) progenitor populations. We first studied hematologically normal bone marrow using the delta culture assay, in which marrow low-density cells were incubated in liquid culture with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) for 1 week, to allow the differentiation of mature progenitors, and thereafter cultured in methylcellulose in the presence of rGM-CSF and recombinant erythropoietin (rEPO). In this assay rIP-10 significantly inhibited the proliferation of normal marrow hemopoietic progenitors in a dose-dependent fashion. However, when fresh normal marrow cells were cultured in methylcellulose without preincubation in liquid culture, rIP-10 did not affect the growth of colony-forming cells. In contrast, when recombinant c-kit ligand (rKL) was added to rGM-CSF and rEPO, an increment in colony numbers was observed that was eliminated by rIP-10. Similar experiments performed with low-density, non-adherent, T cell-depleted AML marrow cells, obtained from 12 untreated adult AML patients, revealed qualitatively similar results: rIP-10 inhibited the proliferation of AML progenitors in the AML delta assay but did not affect the growth of rGM-CSF-responsive AML colony-forming cells when plated in semisolid media in the presence of rGM-CSF. When rKL was added to rGM-CSF during plating in an effort to recruit additional AML progenitor populations, there was an increment in leukemic blast colony numbers that was eliminated by rIP-10. As observed with normal progenitors, the effect of rIP-10 on these AML progenitors was concentration-dependent, statistically significant and reversible with a rIP-10-neutralizing antiserum. To delineate the mechanism of action of rIP-10 we used the thymidine suicide assay and found that rIP-10 significantly reduced the fraction of leukemic progenitors synthesizing DNA. Our data suggest the rIP-10 inhibits the proliferation of (probably immature) AML progenitor populations by reducing the fraction of cells undergoing DNA synthesis. Additional studies are needed to further elucidate the mechanism of this inhibition and to determine the potential clinical benefits of rIP-10 in future therapies for AML.

Acute Disease↗
PubMed1996

Results with high-dose chemotherapy and unpurged autologous stem cell transplantation in 73 patients with chronic myelogenous leukemia: the MD Anderson experience.

The purpose of this study was to evaluate the effectiveness of unpurged autologous stem cell transplantation (ASCT) for chronic myelogenous leukemia (CML) and its impact on the survival of patients in first and late chronic phase (CML-CP) including those resistant to or unable to tolerate interferon alfa (IFN-alpha) therapy. Between 1982 and 1993, 73 patients with CML who underwent ASCT were evaluated. Twenty-eight patients had signs of transformation, 20 were in second or subsequent CP, 22 had CML-CP and had shown resistance to or were unable to tolerate IFN-alpha therapy, and there had Philadelphia (Ph) chromosome-negative CML. Survival of patients in CML-CP who underwent ASCT was compared to controls who were in first CP receiving INF-a therapy. Patients and controls were matched for age, decade of therapy, response to IFN-alpha therapy (resistance vs toxicity) and the time to ASCT (study group) vs time to resistance (control group). Nine 12% patients failed to achieve hematologic recovery, and five (7%) had early death secondary to toxicity. Twenty-seven (58%) patients who received transplants in advanced-stage CML and 18 (82%) transplanted in CML-CP achieved complete hematologic remission (CHR). The incidence of complete cytogenetic response was 10 and 14%, respectively. The median survival of these two groups of patients was 5 and 34 months, respectively (P < 0.001). However, the survival of patients in CML-CP was not significantly different from controls (34 vs 49 months; P = 0.17). We conclude that unpurged ASCT does not prolong the survival of patients in CML-CP who are resistant to IFN-alpha therapy. Progress in autotransplantation in CML might require innovative approaches to eradicate the leukemic cells from the autologous stem cells prior to transplants.

Adolescent↗
PubMed1996

Molecular and biologic characterization of a newly established Philadelphia-positive acute lymphoblastic leukemia cell line (Z-33) with an autocrine response to GM-CSF.

We have recently established a new Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) cell line, designated Z-33. This line has L2 morphology, ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1-positive ALL patient from whom the line was derived. In addition, a rearranged immunoglobulin heavy-chain gene (JH) band was found in Z-33 cells by Southern blot analysis, confirming B cell clonality. Cytogenetic analysis of the cell line revealed t(9;22)(q34;q11.2). Polymerase chain reaction (PCR)-amplified cDNA from Z-33 cells demonstrated an e1-az BCR-ABL junction, and the p190BCR-ABL protein was detected in them by the immune complex kinase assay. Z-33 cells produce interleukin (IL)-1 beta, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta, Neither IL-1 beta, G-CSF, TNF-alpha, nor their corresponding antibodies affected the cell line's growth. In contrast, anti-GM-CSF neutralizing antibodies suppressed Z-33 colony formation, and GM-CSF stimulated it in a dose-dependent fashion. In addition, receptor studies with biotinylated GM-CSF demonstrated specific binding to Z-33 cells, indicating that the cells express GM-CSF receptors. Taken together, our data suggest that the Ph1-positive Z-33 ALL cells produce GM-CSF, express GM-CSF receptors, and show an autocrine proliferative response to this cytokine.

Antibodies↗
PubMed1996

Role of interleukin-1 beta converting enzyme (ICE) in leukemia.

Interleukin (IL)-1 is a proinflammatory cytokine that plays a pivotal role in driving the in vitro proliferation of leukemic cells through autocrine or paracrine pathways. Both IL-1 genes, IL-1 alpha and the prominent IL-1 beta, produce 31 kDa proteins. Whereas the precursor (pro) 31 kDa form of IL-1 alpha is biologically active, pro-IL-1 beta is inactive unless cleaved to its mature form by a cytoplasmic cysteine protease termed IL-1 beta converting enzyme (ICE). Although ICE was first thought to be a unique enzyme with a single biologic activity, several investigators have demonstrated that ICE shares sequence homology with the protein product of ced-3, the gene for cell death of the nematode Caenorhabditis elegans, and can induce apoptosis in different cellular systems. However, recent data indicate that ICE is a member of an increasingly recognized family of ICE-related molecules whose other members, such as CPP32, do not cleave pro-IL-1 beta but rather are effective inducers of apoptotic cell death. We recently investigated the effect of ICE inhibition on acute myelogenous leukemia (AML) colony growth. We found that inhibition of ICE reduced the production of mature IL-1 beta and suppressed the proliferation of AML colony-forming units, confirming the central role of IL-1 beta in AML progenitor proliferation. These data suggest that the primary role of ICE in AML cells is cleavage of pro-IL-1 beta rather than induction of apoptosis and that the antileukemic activity of specific ICE inhibitors warrants further exploitation.

Animals↗
PubMed1995

Effect of interleukin-1 beta converting enzyme inhibitor on acute myelogenous leukemia progenitor proliferation.

Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) is a cysteine protease that specifically cleaves precursor IL-1 beta to its biologically active form. Recent studies have also implicated ICE in the induction of apoptosis in vertebrate cells. Because IL-1 plays a major role in acute myelogenous leukemia (AML) blast proliferation, we sought to investigate the effect of ICE inhibition on AML progenitors. To do this, we used bocaspartyl (benzyl) chloromethylketone (BACMK) an inhibitor designed to penetrate cells and bind covalently to the active site of ICE. Our preliminary experiments showed that incubation of activated peripheral blood cells with 2.5 mumol/L of BAMCK downregulated production of mature IL-1 beta but had no effect on tumor necrosis factor-alpha. To test the effects of the inhibitor on AML cells, we first used the OCI/AML3 cell line. We found that these cells produce IL-1 beta and bind the biotinylated cytokine and that IL-1 inhibitors, such as IL-1 neutralizing antibodies, IL-1 receptor antagonist, and soluble IL-1 receptors, specifically inhibit OCI/AML3 proliferation, indicating that IL-1 beta is an autocrine growth factor for OCI/AML3 cells. The ICE inhibitor suppressed OCI/AML3 growth in a dose-dependent manner (at 0.4 to 4 mumol/L) and downregulated mature IL-1 beta production, as assessed by Western immunoblotting. Similar results were obtained with marrow aspirates from 16 AML patients. The ICE inhibitor suppressed proliferation of AML precursors (by up to 78%; mean, 44%) in a dose-dependent fashion at concentrations ranging from 0.4 to 5 mumol/L but not proliferation of normal marrow progenitors; the suppressive effect was reversed by IL-1 beta. Furthermore, incubation of AML cells with 4 mumol/L BAMCK downregulated the production of mature IL-1 beta, suggesting that the growth-inhibitory effect is mediated through suppression of the biologically active cytokine. Our data indicate that inhibition of ICE suppresses AML blast proliferation and suggest that ICE inhibitors may have a role in future therapies for AML.

Adult↗
PubMed1995

CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation.

Donor lymphocyte infusions can reinduce complete remission in the majority of patients with chronic myelogenous leukemia (CML) who relapse into chronic phase after allogeneic bone marrow transplantation (BMT). Such infusions are associated with a high incidence of graft-versus-host disease (GVHD) and marrow aplasia. BMT using selective depletion of CD8+ lymphocytes from donor cells reduces the incidence of GVHD without an increase in leukemia relapse. We hypothesized that infusion of CD8-depleted donor peripheral blood lymphocytes could also reinduce complete remissions with a lesser potential to produce symptomatic GVHD in patients with CML who relapsed after allogeneic BMT. Ten patients with Ph(+) CML who relapsed a median of 353 days after BMT (range, 82 to 1,096 days) received donor lymphocyte infusions depleted of CD8+ cells. Nine patients received a single infusion and 1 received two infusions. Four patients were treated while in chronic phase with clonal evolution, 2 during accelerated phase, 3 during blast crisis, and 1 in a cytogenetic relapse. A mean of 0.9 +/- 0.3 x 10(8) mononuclear cells/kg were infused, containing 0.6 +/- 0.4 x 10(6) CD3+CD8+ cells/kg. Six patients achieved hematologic and cytogenetic remission at 4, 8, 11, 15, 39, and 54 weeks after lymphocyte infusion. Two patients developed > or = grade II acute GVHD, and 1 patient developed mild chronic GVHD. We conclude that donor lymphocyte infusions depleted of CD8+ cells can induce remissions with a low rate of severe acute GVHD in patients with CML who relapse after allogeneic BMT, supporting the hypothesis that CD8+ lymphocytes are important effectors of GVHD, but may not be essential for the graft-versus-leukemia effect against this disease. Further controlled studies are required to confirm these preliminary observations.

Acute Disease↗
PubMed1995

Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase.

Homoharringtonine (HHT) is a plant alkaloid with potent myelosuppressive activity and little toxicity when used in a continuous infusion schedule. The antileukemic efficacy of HHT has been shown in acute myeloid leukemia, but has not been investigated in chronic myelogenous leukemia (CML). Seventy-one patients with Philadelphia chromosome-positive (Ph+) CML in late chronic phase (time from diagnosis to therapy longer than 12 months) were treated with a continuous infusion of HHT at a daily dose of 2.5 mg/m2 for 14 days for remission induction and for 7 days every month for maintenance. The median number of courses given was 6 (range, 1 to 35) and 21 patients (30%) continue on treatment. Forty-two of 58 patients (72%) evaluable for hematologic response achieved a complete hematologic remission, and 9 (16%) had a partial hematologic remission. Twenty-two of 71 patients (31%) developed a cytogenetic response; it was major (Ph+ cells less than 35%) in 11 (15%) and complete (Ph+ cells 0%) in 5 (7%). Significant myelosuppression occurred in 39% of induction courses and 9% of maintenance courses. Fever or documented infection was present in 26% of induction courses and in only 8% of maintenance courses. Nonmyelosuppressive toxicity was minimal. Homoharringtonine produced hematologic remissions in the majority of patients with advanced chronic-phase CML. Cytogenetic response occurred in some patients without an association with myelosuppression, and these responses may be prolonged. Future studies investigating homoharringtonine in combination with other active agents in CML, such as interferon, are warranted.

Adult↗
PubMed1995

The breakpoint cluster region site in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Clinical, laboratory, and prognostic correlations.

BACKGROUND: The breakpoint site of the breakpoint cluster region (bcr) has been correlated with patient characteristics, with the disease phase, and with the prognosis of patients with chronic myelogenous leukemia (CML), but the findings remain controversial. METHODS: Appropriate restriction enzymes and the 3' and universal probes were used to map the breakpoint site by Southern blot analysis into 5' and 3' breakpoints and a breakpoint in zone 3 (or fragment 2) in 362 patients in different phases of CML (238 in early chronic phase, 69 in late chronic phase, 31 in accelerated phase, and 24 in blastic phase). Standard statistical methods were used to evaluate differences in characteristics and in prognosis by the breakpoint site. RESULTS: No correlation was noted between CML phases and breakpoint site. Among patients in the early chronic phase, thrombocytosis was significantly associated with the 3' breakpoint site (P = 0.02), whereas peripheral basophilia occurred more frequently with the 5' breakpoint site (P = 0.05). Other patient and disease characteristics were similar in frequency among the breakpoint-site subgroups. There was no difference in response to alpha-interferon therapy (186 patients treated) by the breakpoint site. Survival, dated from either referral to the authors' institution or from diagnosis, was not significantly different among patients with early chronic phase CML by the breakpoint site. However, patients with a 3' deletion tended to have a shorter survival. CONCLUSION: Determination of the breakpoint site by Southern blot analysis does not help to predict prognosis of patients with CML.

Chromosomes, Human, Pair 22↗
PubMed1995

Hypermetaphase fluorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment.

Using Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) as a model, our aim has been to develop a molecular cytogenetic method of high resolution analysis for monitoring the frequency of cells with nonrandom chromosome rearrangements in the bone marrow of patients receiving treatment for hematologic malignancies. Long-term exposure (24 hours) of bone marrow cultures to colcemid (0.1 microgram/mL) maximized a high frequency of metaphase collection. Such preparations were subjected to fluorescence in situ hybridization (FISH) using a 5 Mb probe that overlapped the region of the translocation at chromosome 9q34. This detected the Ph translocation in the resultant large number of overly contracted chromosome spreads. The procedure was validated and verified by studying 70 double-blind marrow samples from patients in different stages of Ph+ CML and from patients with Ph- hematologic malignancies (controls). This hypermetaphase FISH (HMF) method clearly identified Ph+ metaphases and allowed the analysis of 500 hypermetaphases per sample in less than 1 hour after FISH. HMF (1) identified statistically significant differences between the frequencies of Ph+ cells in samples that differed by less than 4%; (2) resolved such differences among patient samples that were all judged 100% Ph+ by standard G-band cytogenetics (CG); (3) resulted in the reclassification of response status in 23% of the patients initially classified by CG; (4) recognized Ph+ cells in 16% of patients characterized as having a complete cytogenetic response and in one patient with an original diagnosis of Ph- CML; and in one patient with an original diagnosis of Ph- CML; and (5) was informative where insufficient metaphases were obtainable for analysis by CG. HMF appears to be uniquely suitable for monitoring the status of patients with CML receiving treatment. It should also be applicable for patients with any hematologic diseases where chromosomal alterations are known and appropriate FISH probes are available.

Azure Stains↗
PubMed1995

Transformation of chronic lymphocytic leukemia to lymphoma of true histiocytic type.

BACKGROUND: Chronic lymphocytic leukemia (CLL) may evolve into large cell lymphoma (Richter's syndrome), prolymphocytic leukemia, acute lymphoblastic leukemia, and myeloma. METHODS: A patient with CLL that transformed into a lymphoma of true histiocytic type is described, and the literature on the association of these two disorders is reviewed. RESULTS: Lymphomas of true histiocytic type developing as an aggressive terminal phase of CLL previously have been reported in nine patients. Fever and rapidly increasing lymphadenopathy and splenomegaly were the most common signs and symptoms. As with de novo lymphoma of true histiocytic type, extranodal involvement of the soft tissue, gastrointestinal tract, kidneys, bone marrow, liver, and lungs was documented among the 10 patients with lymphoma of true histiocytic type transformed from CLL. The median interval between diagnosis of CLL and the evolution to lymphoma of true histiocytic type was 25.5 months. Patients with lymphomas of true histiocytic type after CLL were treated with fludarabine and various other combination chemotherapy regimens with only short-lived responses. The median time to death after transformation was only 33 days (range, 10 days to 5 months). CONCLUSION: Lymphomas of true histiocytic type appear to represent an additional, though uncommon, form of transformation in CLL. Although their presentation is reminiscent of other intermediate to high grade lymphomas, they can be distinguished based on their morphologic and immunophenotypic features. In the patients described in this study to date, transformation of CLL to lymphomas of true histiocytic type is a poor prognostic sign, with survival generally of only days to weeks.

Bone Marrow↗